Synthetic Excipients Challenge All-Natural Organics Synthetic ...

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Special Report An excipient's path to the National Formulary After a new excipient has been used in an FDA-approved drug, the excipient manufacturer can submit a monograph of the excipient to the United States Pharmacopeia (USP). USP's web site, www.usp.org, posts the requirements for new submissions, called “Requests for Revision,” and details what should be included in the submission package. Once USP receives the company's submission, it first makes an initial evaluation of the completeness of the data. If it determines that all the required data are included, it will send the submission on to an expert committee for review. The committees are generally composed of representatives from the pharmaceutical manufacturing industry, government (including FDA), and academia. The expert committee will then make a more-thorough evaluation of the submission package. If accepted, it will be incorporated in the Pharmacopeial Forum (PF), which is published every other month, for public review and comment. Anyone with an interest in that excipient, called a stakeholder, can send comments, but those comments must be substantiated with appropriate data or reasonable information. After the comments are received, the complete package is sent back to the expert committee. If there are no comments, the monograph proposal is voted on by the expert committee to become an official monograph in the USP–NF after a minimum of 60 days (typically 90 days) have passed since its publication in the PF. When there are comments, the committee will decide whether to revise the monograph accordingly or to reject them. If the monograph is revised, then it must be published in the PF a second time, then can be voted to become an official monograph 60 days after publication. If a monograph requires only one publication in the PF, it can become official in approximately 6–8 months. When a second publication cycle is required, the entire process can take 15 months or longer. Excipient manufacturers easily disagree with these definitions when describing their products because so much chemistry is involved in the manufacturing process. As a result, the term synthetic is frequently used to encompass both types. Applications and advantages Synthetic excipients are used in the manufacture of tablets to bind the tablet together, reduce diewall friction between the tablet and the tableting press, control pH balance, and to disintegrate the tablet in the stomach once it has been ingested. They’re used for just about every function of an inactive ingredient except as bulking agents, which are usually natural products. In parenterals, synthetics are used as solubilization agents to make actives more soluble, and therefore, more deliverable. Synthetics also offer other benefits over natural excipients. Because they’re not extracted from animal materials, they’re free of transmissible diseases—a characteristic that may be of increased importance among manufacturers and regulators in light of the recent case of a BSEinfected cow found in the United States last year. The absence of plant or animal material in synthetics also eliminates concerns posed by genetically modified organisms (GMOs), which can also interfere with the safety and acceptability of a drug formulation. Another benefit of synthetics compared with natural excipients is that they can be produced to a certain specification because there is more control over the manufacturing process. Most naturalbased polymers aren’t chemically identical because of the variability that exists in nature. For example, depending on changes in weather from one year to the next, the structure and properties of natural materials can also vary slightly—an effect avoided with synthetics, which are synthesized in chemical reactors. Joseph Zeleznik, senior scientist at excipients manufacturer JRS Pharma (Patterson, NY), points to magnesium stearate as a good example of a natural material versus a synthetic. “Manufacturing controls are just not that stringent because they can’t be. Because magnesium stearate is a naturally derived product, it possesses a great deal of inherent variability—not only from batch to batch but from manufacturer to manufacturer as well,” says Zeleznik. Such variability in natural excipients can be problematic for drug manufacturers because once their formulation has been approved by FDA, it becomes difficult to change the formulation components or component levels that were used in the clinical trials. If any variability exists, either in the raw materials or manufacturing process, a company will have to spend more time and money proving that there are no adverse effects as a result of the change. 40 Pharmaceutical Technology APRIL 2004 www.pharmtech.com
Special Report Lipophilic drugs form an equilibrium complex with the lipophilic cavity of cyclodextrin molecules, minimizing their interaction with water. The hydrophilic nature of the exterior of the cyclodextrin provides water solubility for the drugcyclodextrin complex. Eric Smith, vice-president of marketing at JRS, agrees with Zeleznik. “Even slight changes, such as in particle size, can affect the drug release profile,” Smith says. “Our industry is really exacting with specifications.” JRS Pharma manufactures the excipient “Pruv” (sodium stearyl fumarate), which is used as a boundary lubricant (i.e., it coats the powder particles in formulations) and also helps reduce interparticulate friction to enhance formulation flow onto the tablet press. “Lubrication is a very sensitive function within the tableting process,” Smith states. “The key is to produce a synthetic material that always delivers the same lubricity level to the formulation.” Because of the sensitivity of the lubrication function, companies impose strict specifications on manufacturing processes to ensure the predictability of products. Bringing new synthetic excipients to market One of the main challenges facing synthetic excipient manufacturers, as they drive toward higher market share, is the difficulty involved in bringing a new synthetic excipient to market. According to Lou Blecher, former chairman of the International Pharmaceutical Excipients Council (IPEC) and now a consultant to excipient manufacturers, this particular challenge is a “virtual impossibility” for synthetics manufacturers. As Blecher explains, because FDA has no regulatory body to review excipients separately from formulations, they’re only approved as part of a new drug application (NDA) or investigational new drug (IND). In addition, the United States Pharmacopeia (USP) will not add any excipients to its National Formulary unless the excipient has been used in at least one FDA-approved product. Although these regulatory issues may sound like obstacles in and of themselves, the real difficulty lies in convincing drug manufacturers to use a new excipient in a formulation. Typically, manufacturers won’t risk product approval with a novel synthetic unless that particular excipient provides a unique function essential to the formulation. “Why would you ask for the extra trouble of having to explain something to the FDA reviewer that he or she has never seen before?” Blecher queries. “It’s much easier to stick with materials that are already accepted than to monkey around with something new.” Lokesh Bhattacharyya, PhD, director of the noncomplex actives and excipients division in the information and standards development program at USP, agrees with Blecher and adds that because the functions of new excipients are less understood, there’s more concern about their affect on the bioavailability of a drug product. “Anything new will get more scrutiny,” he says. “A new excipient will require a greater level of categorization.” Finding profitable applications. For a drug manufacturer to consider using a novel synthetic excipient (a brand new chemical that has not been used in drugs before), the excipient manufacturer will have to develop the same amount of safety data required for a new drug, which is both costly and time consuming. This fact alone prevents many synthetics providers from developing new products unless there’s a specific application for the novel excipient that can outweigh the costs of safety testing and prove profitable for the company.“If it’s not the only thing permitting an antitumor agent from being marketed, are you going to spend the money looking?” asks Blecher. CyDex, Inc. (Lenexa, KS) decided it would spend the money when it produced its novel excipient, “Captisol” (modified beta-cyclodextrin). Captisol, which is considered a semisynthetic excipient because it’s a chemical modification of parent cyclodextrins that occur in nature, works as a solubilization agent, allowing anticancer agents to be delivered parenterally to the body. The development of Captisol was motivated by an overall interest in the use of cyclodextrins for parenteral formulations. Beta-cyclodextrin can’t be used in parenteral formulations because, upon systemic administration, it causes extensive hemolysis and dramatic nephrotoxicity. Researchers such as those at the University of Kansas explored modifications of the parent cyclodextrins in search of derivatives that would have good systemic safety profiles while retaining or improving the functional complexation characteristics of the parent cyclodextrins. Because the safe delivery of anticancer agents is such a strong need in the industry, CyDex decided it was a viable application for this type of excipient. Doug Hecker, director of operations at CyDex, states that it’s best for a manufacturer if an application for a new excipient comes from the customers themselves.“It’s easier to solve a known problem than to try to find a problem and then 42 Pharmaceutical Technology APRIL 2004 www.pharmtech.com
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